tbuckley/cabot-search huggingface dataset:
Structural surfaceomics reveals an AML-specific conformation of integrin β2 as a CAR T cellular therapy target
Authors: Kamal Mandal, Gianina Wicaksono, Clinton Yu, Jarrett J. Adams, Michael R. Hoopmann, William C. Temple, Adila Izgutdina, Bonell Patiño Escobar, Maryna Gorelik, Christian H. Ihling, Matthew A. Nix, Akul Naik, William H. Xie, Juwita Hübner, Lisa A. Rollins, Sandy M. Reid, Emilio Ramos, Corynn Kasap, Veronica Steri, Juan Antonio Camara Serrano, Fernando Salangsang, Paul Phojanakong, Melanie McMillan, Victor Gavallos, Andrew D. Leavitt, Aaron C. Logan, Cliona M. Rooney, Justin Eyquem, Andrea Sinz, Benjamin J. Huang, Elliot Stieglitz, Catherine C. Smith, Robert L. Moritz, Sachdev S. Sidhu, Lan Huang, Arun P. Wiita
Journal: Nature Cancer (2023)

Abstract Safely expanding indications for cellular therapies has been challenging given a lack of highly cancer-specific surface markers. Here we explore the hypothesis that tumor cells express cancer-specific surface protein conformations that are invisible to standard target discovery pipelines evaluating gene or protein expression, and these conformations can be identified and immunotherapeutically targeted. We term this strategy integrating cross-linking mass spectrometry with glycoprotein surface capture ‘structural surfaceomics’. As a proof of principle, we apply this technology to acute myeloid leukemia (AML), a hematologic malignancy with dismal outcomes and no known optimal immunotherapy target. We identify the activated conformation of integrin β 2 as a structurally defined, widely expressed AML-specific target. We develop and characterize recombinant antibodies to this protein conformation and show that chimeric antigen receptor T cells eliminate AML cells and patient-derived xenografts without notable toxicity toward normal hematopoietic cells. Our findings validate an AML conformation-specific target antigen and demonstrate a tool kit for applying these strategies more broadly.
Outcomes Following Early Postoperative Adjuvant Radiosurgery for Brain Metastases
Authors: Evan D. Bander, Tarek Y. El Ahmadieh, Justin Chen, Anne S. Reiner, Samantha Brown, Alexandra M. Giantini-Larsen, Robert J. Young, Kathryn Beal, Brandon S. Imber, Luke R. G. Pike, Cameron W. Brennan, Viviane Tabar, Katherine S. Panageas, Nelson S. Moss
Journal: JAMA Network Open (2023)

Importance Adjuvant stereotactic radiosurgery (SRS) enhances the local control of resected brain metastases (BrM). However, the risks of local failure (LF) and potential for posttreatment adverse radiation effects (PTRE) after early postoperative adjuvant SRS have not yet been established. Objective To evaluate whether adjuvant SRS delivered within a median of 14 days after surgery is associated with improved LF without a concomitant increase in PTRE. Design, Setting, and Participants This prospective cohort study examines a clinical workflow (RapidRT) that was implemented from 2019 to 2022 to deliver SRS to surgical patients within a median of 14 days, ensuring all patients were treated within 30 days postoperatively. This prospective cohort was compared with a historical cohort (StanRT) of patients with BrM resected between 2013 and 2019 to assess the association of the RapidRT workflow with LF and PTRE. The 2 cohorts were combined to identify optimal SRS timing, with a median follow-up of 3.3 years for survivors. Exposure Timing of adjuvant SRS (14, 21, and 30 days postoperatively). Main Outcomes and Measures LF and PTRE, according to modified Response Assessment in Neuro-Oncology Brain Metastases criteria. Results There were 438 patients (265 [60.5%] female patients; 23 [5.3%] Asian, 27 [6.2%] Black, and 364 [83.1%] White patients) with a mean (SD) age of 62 (13) years; 377 were in the StanRT cohort and 61 in the RapidRT cohort. LF and PTRE rates at 1 year were not significantly different between RapidRT and StanRT cohorts. Timing of SRS was associated with radiographic PTRE. Patients receiving radiation within 14 days had the highest 1-year PTRE rate (18.08%; 95% CI, 8.31%-30.86%), and patients receiving radiation between 22 and 30 days had the lowest 1-year PTRE rate (4.10%; 95% CI, 1.52%-8.73%; P = .03). LF rates were highest for patients receiving radiation more than 30 days from surgery (10.65%; 95% CI, 6.90%-15.32%) but comparable for patients receiving radiation within 14 days, between 15 and 21 days, and between 22 and 30 days (≤14 days: 5.12%; 95% CI, 0.86%-15.60%; 15 to ≤21 days: 3.21%; 95% CI, 0.59%-9.99%; 22 to ≤30 days: 6.58%; 95% CI, 3.06%-11.94%; P = .20). Conclusions and Relevance In this cohort study of adjuvant SRS timing following surgical resection of BrM, the optimal timing for adjuvant SRS appears to be within 22 to 30 days following surgery. The findings of this study suggest that this timing allows for a balanced approach that minimizes the risks associated with LF and PTRE.
R-CODOX-M/R-IVAC versus DA-EPOCH-R in patients with newly diagnosed Burkitt lymphoma (HOVON/SAKK): final results of a multicentre, phase 3, open-label, randomised trial
Authors: Martine E D Chamuleau, Frank Stenner, Dana A Chitu, Urban Novak, Monique C Minnema, Paul Geerts, Wendy B C Stevens, Thorsten Zenz, Gustaaf W van Imhoff, Ka Lung Wu, Astrid M P Demandt, Marie Jose Kersten, Wim E Terpstra, Lidwine W Tick, Dries Deeren, Eric Van Den Neste, Michael Gregor, Hendrik Veelken, Lara H Böhmer, Clemens B Caspar, Pim Mutsaers, Jeannine M Refos, Robby Sewsaran, Liping Fu, Rianne L Seefat, Carin A Uyl-de Groot, Stefan Dirnhofer, Michiel Van Den Brand, Daphne de Jong, Marcel Nijland, Pieternella Lugtenburg
Journal: The Lancet Haematology (2023)
Retraction Note: The LINC00623/NAT10 signaling axis promotes pancreatic cancer progression by remodeling ac4C modification of mRNA
Authors: Zengyu Feng, Kexian Li, Kai Qin, Juyong Liang, Minmin Shi, Yang Ma, Shiwei Zhao, Huaiyu Liang, Dongni Han, Baiyong Shen, Chenghong Peng, Hao Chen, Lingxi Jiang
Journal: Journal of Hematology & Oncology (2023)
Hepatocellular Carcinoma Patients with Hepatitis B Virus Infection Exhibited Favorable Survival from Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis
Authors: Qi Du, Jia Yuan, Zhenggang Ren
Journal: Liver Cancer (2023)

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; Immune checkpoint inhibitors (ICIs) have demonstrated effectiveness for advanced hepatocellular carcinoma (HCC). However, the discrepancy in the efficacy of ICIs in HCC patients with distinct etiologies has not been systematically validated. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; PubMed, MEDLINE, Embase, &lt;ext-link ext-link-type="uri" xlink:href="http://clinicaltrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink"&gt;clinicaltrials.gov&lt;/ext-link&gt;, and abstracts from ASCO and ESMO conferences were searched for eligible trials that explored the impact of etiology factor on the ICI treatment in HCC patients. The pooled hazard ratio (HR) of overall survival (OS) and progression-free survival (PFS), as well as the pooled odds ratio (OR) of objective response rate (ORR), were calculated with stratification of hepatitis B virus (HBV), hepatitis C virus (HCV) and nonviral subgroup, and the heterogeneity between different etiological subgroups was assessed by using an interaction test. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Eight eligible studies with a total of 5,646 patients were identified from searching published articles and conference abstracts. ICI therapies were associated with significantly prolonged OS with the pooled HRs of 0.78 (95% CI 0.73–0.84, &lt;i&gt;p&lt;/i&gt; &amp;lt; 0.001), 0.71 (95% CI 0.65–0.79, &lt;i&gt;p&lt;/i&gt; &amp;lt; 0.001), 0.80 (95% CI 0.69–0.93, &lt;i&gt;p&lt;/i&gt; = 0.003), and 0.87 (95% CI 0.77–0.97, &lt;i&gt;p&lt;/i&gt; = 0.011) for the whole population, HBV subgroup, HCV subgroup, and non-viral subgroup, respectively. In addition, this analysis reported a significant PFS improvement with ICI therapies with HRs of 0.78 (&lt;i&gt;p&lt;/i&gt; = 0.004), 0.53 (&lt;i&gt;p&lt;/i&gt; &amp;lt; 0.001), 0.65 (&lt;i&gt;p&lt;/i&gt; = 0.011), and 0.81 (&lt;i&gt;p&lt;/i&gt; = 0.107) for whole population, HBV, HCV, and nonviral subgroup, respectively. The HBV-related HCC patients showed the more distinctive HRs for OS and PFS than other etiology subgroups, and this difference was significant in PFS (&lt;i&gt;p&lt;/i&gt; for heterogeneity = 0.001), and there was a tendency of significance in OS (&lt;i&gt;p&lt;/i&gt; for heterogeneity = 0.079). Furthermore, the ORR advantages of ICI therapies over control were also confirmed with the pooled ORs of 3.62 (&lt;i&gt;p&lt;/i&gt; &amp;lt; 0.001), 3.84 (&lt;i&gt;p&lt;/i&gt; &amp;lt; 0.001), 3.05 (&lt;i&gt;p&lt;/i&gt; &amp;lt; 0.001), and 2.99 (&lt;i&gt;p&lt;/i&gt; &amp;lt; 0.001) for whole population, HBV, HCV, and nonviral population, respectively (&lt;i&gt;p&lt;/i&gt; for heterogeneity = 0.743). &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; ICI therapies significantly improve OS, PFS, and ORR for HCC patients with different etiologies. HBV-related HCC patients could be the highlighted population to benefit from ICI treatment.
Impact of Liver Fibrosis Severity on Oncological Prognosis in Hepatocellular Carcinoma
Authors: Koya Yasukawa, Akira Shimizu, Koji Kubota, Tsuyoshi Notake, Kiyotaka Hosoda, Hikaru Hayashi, Yuji Soejima
Journal: Liver Cancer (2023)

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Cirrhosis is deemed to be a contributing factor to the postoperative recurrence of hepatocellular carcinoma (HCC); however, the precise impact of liver fibrosis on both cancer-specific prognoses remains unclear. This investigation sought to elucidate the effect of liver fibrosis severity on the cancer-specific prognosis. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; A total of 524 consecutive patients were included. Recurrence-free survival (RFS) and disease-specific survival (DSS) were compared according to fibrosis stage. Moreover, postoperative outcomes were subjected to analysis in cohorts of patients with F0 and F1–3, as well as in those with F1–3 and F4, who were carefully matched for background factors. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; The 5-year RFS exhibited a significantly worse outcome in the F4 group compared to other stages of fibrosis: 5-year RFS – F0 (46.6%), F1–3 (33.1%), and F4 (23.5%), &lt;i&gt;p&lt;/i&gt; = 0.03 (F0 vs. F1–3) and &lt;i&gt;p&lt;/i&gt; &amp;lt; 0.01 (F1–3 vs. F4). Additionally, the 5-year DSS also presented a significantly worse prognosis in the F4 group: 5-year DSS – F0 (82.9%), F1–3 (73.6%), and F4 (57.4%), &lt;i&gt;p&lt;/i&gt; = 0.04 (F0 vs. F1–3) and &lt;i&gt;p&lt;/i&gt; &amp;lt; 0.01 (F1–3 vs. F4). In multivariate analysis, fibrosis 1, 2, 3, and 4 stage (compared with F0) (HR: 1.70, 1.81, 1.89, and 3.99, 95% confidence interval: 1.10–1.99, 1.39–2.22, 1.41–2.55, and 2.25–5.01, &lt;i&gt;p&lt;/i&gt; = 0.022, &lt;i&gt;p&lt;/i&gt; = 0.008, &lt;i&gt;p&lt;/i&gt; &amp;lt; 0.001, and &lt;i&gt;p&lt;/i&gt; &amp;lt; 0.001, respectively) was independent risk factor for RFS. After matched analysis, both RFS and DSS exhibited significantly worse prognoses in the presence of more advanced fibrosis. There was a significantly higher incidence of multiple recurrences in the F4 group than the F1–3 group, and a number of recurrences were observed both in the same hepatic segment as the resected side and in the contralateral lobe in F4 group. &lt;b&gt;&lt;i&gt;Discussion/Conclusion:&lt;/i&gt;&lt;/b&gt; The hazard and recurrence pattern of HCC signifies that the prognosis could potentially be poor, as the hepatic fibrosis likely owing to a higher hepatocarcinogenic potential, even in the absence of progression to cirrhotic condition. The risk of de novo recurrence may also increase with the progression of this fibrosis.
Kidney-Specific Interleukin-17 Responses During Infection and Injury
Authors: Doureradjou Peroumal, Partha S. Biswas
Journal: Annual Review of Immunology (2023)

The kidneys are life-sustaining organs that are vital to removing waste from our bodies. Because of their anatomic position and high blood flow, the kidneys are vulnerable to damage due to infections and autoinflammatory conditions. Even now, our knowledge of immune responses in the kidney is surprisingly rudimentary. Studying kidney-specific immune events is challenging because of the poor regenerative capacity of the nephrons, accumulation of uremic toxins, and hypoxia- and arterial blood pressure-mediated changes, all of which have unexpected positive or negative impacts on the immune response in the kidney. Kidney-specific defense confers protection against pathogens. On the other hand, unresolved inflammation leads to kidney damage and fibrosis. Interleukin-17 is a proinflammatory cytokine that has been linked to immunity against pathogens and pathogenesis of autoinflammatory diseases. In this review, we discuss current knowledge of IL-17 activities in the kidney in the context of infections, autoinflammatory diseases, and renal fibrosis.
Effect of Hyperthermic Intraperitoneal Chemotherapy on Cytoreductive Surgery in Gastric Cancer With Synchronous Peritoneal Metastases: The Phase III GASTRIPEC-I Trial
Authors: Beate Rau, Hauke Lang, Alfred Koenigsrainer, Ines Gockel, Horst-Guenter Rau, Hendrik Seeliger, Christian Lerchenmueller, Daniel Reim, Roger Wahba, Martin Angele, Steffen Heeg, Tobias Keck, Arved Weimann, Stefan Topp, Pompiliu Piso, Andreas Brandl, Silke Schuele, Peter Jo, Johann Pratschke, Sandra Wegel, Alexander Rehders, Nicolas Moosmann, Jochen Gaedcke, Volker Heinemann, Evelyn Trips, Markus Loeffler, Peter Michael Schlag, Peter Thuss-Patience
Journal: Journal of Clinical Oncology (2023)

In patients with peritoneal metastasis (PM) from gastric cancer (GC), chemotherapy is the treatment of choice. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are still being debated. This randomized, controlled, open-label, multicenter phase III trial (EudraCT 2006-006088-22; ClinicalTrials.gov identifier: NCT02158988) explored the impact on overall survival (OS) of HIPEC after CRS.
Ofranergene Obadenovec (Ofra-Vec, VB-111) With Weekly Paclitaxel for Platinum-Resistant Ovarian Cancer: Randomized Controlled Phase III Trial (OVAL Study/GOG 3018)
Authors: Rebecca C. Arend, Bradley J. Monk, Ronnie Shapira-Frommer, Ashley F. Haggerty, Edwin A. Alvarez, Amnon Amit, Angeles Alvarez Secord, Carolyn Muller, Antonio Casado Herraez, Thomas J. Herzog, Krishnansu S. Tewari, Joshua G. Cohen, Marilyn Huang, Adelya Yachnin, Laura L. Holeman, Jonathan A. Ledermann, Tamar Rachmilewitz Minei, Marc Buyse, Shifra Fain Shmueli, Michal Lavi, Dror Harats, Richard T. Penson, Bhavana Pothuri, Jean-Marie Stephan, Michael Callahan, William Bradley, Purificacion Estevez, Mayu Yunokawa, Setsuko Chambers, Laura Holman, Lisa Landrum, Jean Seidel, Samuel Lentz, Lisa Barroilhet, Georgia McCann, Ora Rosengarten, Daliah Tsoref, Joseph Lucci, Joyce Barlin, Evelyn Fleming, Linda Van Le, Veena John, Cristina Churucca, Pawel Blecharz, Shani Breuer, Thomas Reid, Mary Cunningham, Andrea Jewell, Frederick Ueland, Michael Teneriello, Thomas Woliver, Iwona Podzielinski, Dana Marie Roque, Thomas Krivak, Heidi Godoy, Marta Gil, Yolanda Garcia, Rodryg Ramlau, Masashi Takano, Shin Nishio, Maria Grosse-Perdekamp, Nicholas Taylor, Sara Perez, Kazuki Sudo, Takashi Matsumoto, Hideki Tokunaga, Shelly Morris, James Barter, Merry Markham, Amy Brown, Julian Schink, Maria Bell, Raul Marquez, Cristina Caballero, Tomasz Kubiatowski, Akira Kikuchi, Kenichi Harano, Masahiro Kagabu, Irina Dimitrova, Jeffrey Elder, Tariq Mahmood, Cheung Wong, Nana Tchabo, Christina Chu, Mark Einstein, John Farley, Charles Anderson, Ignacio Romero Noguera, Hidemichi Watari, Shiro Suzuki, Tsuyoshi Saito
Journal: Journal of Clinical Oncology (2023)

To evaluate the addition of ofranergene obadenovec (ofra-vec, VB-111), a novel gene-based anticancer targeted therapy, to once a week paclitaxel in patients with recurrent platinum-resistant ovarian cancer (PROC).
Results of a randomized double-blind placebo-controlled Phase 2 study propose iptacopan as an alternative complement pathway inhibitor for IgA nephropathy
Authors: Hong Zhang, Dana V. Rizk, Vlado Perkovic, Bart Maes, Naoki Kashihara, Brad Rovin, Hernán Trimarchi, Ben Sprangers, Matthias Meier, Dmitrij Kollins, Olympia Papachristofi, Julie Milojevic, Guido Junge, Prasanna Kumar Nidamarthy, Alan Charney, Jonathan Barratt
Journal: Kidney International (2023)

Targeting the alternative complement pathway is an attractive therapeutic strategy given its role in the pathogenesis of immunoglobulin A nephropathy (IgAN). Iptacopan (LNP023) is an oral, proximal alternative complement inhibitor that specifically binds to Factor B. Our randomized, double-blind, parallel-group adaptive Phase 2 study (NCT03373461) enrolled patients with biopsy-confirmed IgAN (within previous three years) with estimated glomerular filtration rates of 30 mL/min/1.73 m
Prognostic and therapeutic potential of senescent stromal fibroblasts in prostate cancer
Authors: Joakin O. Mori, Isra Elhussin, W. Nathaniel Brennen, Mindy K. Graham, Tamara L. Lotan, Clayton C. Yates, Angelo M. De Marzo, Samuel R. Denmeade, Srinivasan Yegnasubramanian, William G. Nelson, Gerald V. Denis, Elizabeth A. Platz, Alan K. Meeker, Christopher M. Heaphy
Journal: Nature Reviews Urology (2023)
Reply: Recognizing the new nomenclature requires a comprehensive analysis of the prevalence, severity, and long-term outlook for SLD and subclassifications
Authors: Brian P. Lee, Jennifer L. Dodge, Norah A. Terrault
Journal: Hepatology (2023)

1Division of Gastroenterology and Liver Diseases, University of Southern California Keck School of Medicine, Los Angeles, CA 2Institute for Addiction Science, University of Southern California, Los Angeles, CA 3Department of Population and Public Health Sciences, University of Southern California Keck School of Medicine, Los Angeles, CA Correspondence Brian P. Lee, University of Southern California, Division of Gastrointestinal and Liver Diseases. Email: [email protected]
Letter to the Editor: Cautious interpretation of the association between finite treatment and better prognosis in initially HBeAg-negative hepatitis B patients with cirrhosis
Authors: Rui Deng, Ziyan Wang, Yuxin Liu, Jian Sun
Journal: Hepatology (2023)

To the editor, We read with great interest the article by Jeng et al, which concluded that finite nucleos(t)ide analogue (Nuc) treatment in HBeAg-negative hepatitis B patients with cirrhosis may reduce HCC incidence.1 This is the first study that reported the long-term outcomes after Nuc discontinuation in patients with cirrhosis; however, several crucial aspects require in-depth clarification and further discussion. Firstly, potential selection bias might limit the reliability and generalizability of the results in this retrospective study. The study design and patient recruitment flowchart did not provide detailed screening strategies and enrollment criteria. We speculate that patients in the "finite group" may discontinue Nuc therapy based on the suggestions of clinicians who may choose patients with better clinical characteristics (no family history, mild cirrhosis, etc.). Secondly, we are concerned that the limited long-term benefits reported by this study may mislead the clinical decision to stop Nuc therapy among HBeAg-negative hepatitis B patients with cirrhosis. According to the majority of well-accepted guidelines,2,3 stopping Nuc therapy was not recommended for patients with cirrhosis due to the risk of liver failure. For patients who are HBeAg-negative, although some studies demonstrated that increased HBsAg loss rate can be achieved after discontinuation, the benefit and risk need to be balanced, especially with the wide coverage of Nuc therapy with low cost and good safety profile.4 Of note, 7 patients died of severe hepatitis flare due to Nuc cessation (5 from the "finite group" and 2 from the "continuous group") in this study. Currently, finite therapy is discouraged in patients who are HBeAg-negative unless they achieve HBsAg loss according to the guidelines recommended by the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL).2,3 Lastly, the authors did not provide enough evidence to support the theory that low-level HBV viremia is beneficial in reducing HCC incidence by promoting specific immunity against HCC. This theory contradicts the consensus that residual HBV DNA during Nuc therapy is associated with higher HCC risk.5 Hence, the goal of antiviral therapy recommended by all guidelines is to achieve complete viral suppression as soon as possible.2,3
A partial form of AIRE deficiency underlies a mild form of autoimmune polyendocrine syndrome type 1
Authors: Bergithe Eikeland Oftedal, Amund Holte Berger, Øyvind Bruserud, Yael Goldfarb, Andre Sulen, Lars Breivik, Alexander Hellesen, Shifra Ben-Dor, Rebecca Haffner-Krausz, Per M Knappskog, Stefan Johansson, Anette Sb Wolff, Eirik Bratland, Jakub Abramson, Eystein Sverre Husebye
Journal: Journal of Clinical Investigation (2023)

Autoimmune polyendocrine syndrome type 1 (APS-1) is caused by mutations in the autoimmune regulator (AIRE) gene. Most patients present with severe chronic mucocutaneous candidiasis and organ-specific autoimmunity from early childhood, but the clinical picture is highly variable. AIRE is crucial for negative selection of T cells, and scrutiny of different patient mutations has previously highlighted many of its molecular mechanisms. In patients with a milder adult-onset phenotype sharing a mutation in the canonical donor splice site of intron 7 (c.879+1G>A), both the predicted altered splicing pattern with loss of exon 7 (AireEx7-/-) and normal full-length AIRE mRNA were found, indicating leaky rather than abolished mRNA splicing. Analysis of a corresponding mouse model demonstrated that the AireEx7-/- mutant had dramatically impaired transcriptional capacity of tissue-specific antigens in medullary thymic epithelial cells but still retained some ability to induce gene expression compared with the complete loss-of-function AireC313X-/- mutant. Our data illustrate an association between AIRE activity and the severity of autoimmune disease, with implications for more common autoimmune diseases associated with AIRE variants, such as primary adrenal insufficiency, pernicious anemia, type 1 diabetes, and rheumatoid arthritis.